Bipolar
Disorder and Alcoholism

Alcohol Research & Health. 2002;26(2): 103-108.

Susan
C. Sonne, PharmD, and Kathleen T. Brady, M.D., Ph.D.

Susan
C. Sonne, PharmD, is a research assistant professor of psychiatry and
behavioral sciences and clinical assistant professor of pharmacy practice,
and Kathleen T. Brady, M.D., Ph.D., is a professor of psychiatry and
behavioral sciences, both at the Medical University of South Carolina,
Center for Drug and Alcohol Programs, Charleston, South Carolina.

Bipolar disorder and
alcoholism commonly cooccur. Multiple explanations for the relationship
between these conditions have been proposed, but this relationship remains poorly
understood. Some evidence suggests a genetic link. This comorbidity also has
implications for diagnosis and treatment. Alcohol use may worsen the clinical
course of bipolar disorder, making it harder to treat. There has been little
research on the appropriate treatment for comorbid patients. Some studies have
evaluated the effects of valproate, lithium, and naltrexone, as well as psychosocial
interventions, in treating alcoholic bipolar patients, but further research
is needed.Key words: comorbidity; manicdepressive psychosis; AODD
(alcohol and other drug dependence); alcoholic beverage; prevalence; genetic
linkage; disease onset; disease course; diagnosis; drug therapy; lithium; valproate;
naltrexone; patient compliance; psychosocial treatment method; literature review

Bipolar disorder and alcoholism
cooccur at higher than expected rates. That is, they cooccur more
often than would be expected by chance and they cooccur more often than
do alcoholism and unipolar depression. This article will explore the relationship
between these disorders, focusing on the prevalence of this comorbidity, potential
theoretical explanations for the high rates of comorbidity, effects of comorbid
alcoholism on the course and features of bipolar disorder, diagnostic issues,
and treatment of comorbid patients.

Bipolar disorder, often
called manic depression, is a mood disorder that is characterized by extreme
fluctuations in mood from euphoria to severe depression, interspersed with periods
of normal mood (i.e., euthymia). Bipolar disorder represents a significant public
health problem, which often goes undiagnosed and untreated for lengthy periods.
In a survey of 500 bipolar patients, 48 percent consulted 5 or more health care
professionals before finally receiving a diagnosis of bipolar disorder, and
35 percent spent an average of 10 years between the onset of illness and diagnosis
and treatment (Lish et al. 1994). Bipolar disorder affects approximately 1 to
2 percent of the population and often starts in early adulthood.

There are a number of
disorders in the bipolar spectrum, including bipolar I disorder, bipolar II
disorder, and cyclothymia. Bipolar I disorder is the most severe; it is characterized
by manic episodes that last for at least a week and depressive episodes that
last for at least 2 weeks. Patients who are fully manic often require hospitalization
to decrease the risk of harming themselves or others. People can also have symptoms
of both depression and mania at the same time. This mixed mania, as it is called,
appears to be accompanied by a greater risk of suicide and is more difficult
to treat. Patients with 4 or more mood episodes within the same 12 months are
considered to have rapid cycling bipolar disorder, which is a predictor of poor
response to some medications. Bipolar II disorder is characterized by episodes
of hypomania, a less severe form of mania, which lasts for at least 4 days in
a row and is not severe enough to require hospitalization. Hypomania is interspersed
with depressive episodes that last at least 14 days. People with bipolar II
disorder often enjoy being hypomanic (due to elevated mood and inflated selfesteem)
and are more likely to seek treatment during a depressive episode than a manic
episode. Cyclothymia is a disorder in the bipolar spectrum that is characterized
by frequent lowlevel mood fluctuations that range from hypomania to lowlevel
depression, with symptoms existing for at least 2 years (American Psychiatric
Association [APA] 1994).

Alcohol dependence, also
known as alcoholism, is characterized by a craving for alcohol, possible physical
dependence on alcohol, an inability to control one's drinking on any given occasion,
and an increasing tolerance to alcohol's effects (APA 1994). Approximately 14
percent of people experience alcohol dependence at some time during their lives
(Kessler et al. 1997). It often starts in early adulthood. Criteria for a diagnosis
of alcohol abuse, on the other hand, do not include the craving and lack of
control over drinking that are characteristic of alcoholism. Rather, alcohol
abuse is defined as a pattern of drinking that results in the failure to fulfill
responsibilities at work, school, or home; drinking in dangerous situations;
and having recurring alcoholrelated legal problems and relationship problems
that are caused or worsened by drinking (APA 1994). The lifetime prevalence
of alcohol abuse is approximately 10 percent (Kessler et al. 1997). Alcohol
abuse often occurs in early adulthood and is usually a precursor to alcohol
dependence (APA 1994).

PREVALENCE OF COMORBIDITY

Several studies have reported
an association between alcoholismand mood disorders. To date, there
have been two large epidemiological studies of psychiatric disorders: the National
Institute of Mental Health's Epidemiologic Catchment Area (ECA) study (Regier
et al. 1990) and the National Comorbidity Survey (NCS) (Kessler et al. 1996).
The ECA study (Regier et al. 1990) revealed that 60.7 percent of people with
bipolar I disorder had a lifetime diagnosis of a substance use disorder (i.e.,
an alcohol or other drug use disorder); 46.2 percent of those with bipolar I
disorder had an alcohol use disorder; and 40.7 percent had a drug abuse or dependence
diagnosis (the percentages of people with alcohol use disorders and drug abuse
disorders do not add to 100 due to overlap). Fortyeight percent of people
with bipolar II disorder had a substance use disorder, 39.2 percent had an alcohol
use disorder, and 21 percent had a drug abuse or dependence diagnosis (these
figures reflect overlap, as above.) As shown in the table, alcohol dependence
was twice as likely to cooccur in people with bipolar spectrum disorders
than in those with unipolar depression (i.e., depression without mania). It
is also noteworthy that bipolar disorder was more likely to occur with alcohol
dependence than with alcohol abuse (see table). As part of the ECA study, Helzer
and Przybeck (1988) found that mania (i.e., bipolar I disorder) and alcohol
use disorders are far more likely to occur together (i.e., 6.2 times more likely)
than would be expected by chance. Of all other psychiatric diagnoses investigated
in this study, only antisocial personality disorder was more likely to be related
to alcoholism than mania. The findings of the NCS with regard to the comorbidity
of mood disorders and alcoholism were very similar.

Comorbid
Mood Disorders* and Substance Abuse

Any
substance abuse or dependence (%)

Alcohol
dependence (%)

Alcohol
abuse (%)

Any
Mood Disorder

32.0

4.9

6.9

Any
Bipolar Disorder

56.1

27.6

16.1

Bipolar
I

60.7

31.5

14.7

Bipolar
II

48.1

20.8

18.4

Unipolar
Depression

27.2

11.6

5.0

NOTES: *Mood disorders
include depression and bipolar disorder.
Bipolar disorder, or manic depression, is characterized by extreme mood
swings.
Bipolar I disorder is the most severe bipolar disorder.
Bipolar II disorder is less severe.
Unipolar depression is depression without manic episodes.
SOURCE: Data reported in the table are based on findings of the Epidemiologic
Catchment Area study (Regier et al. 1990).

POSSIBLE EXPLANATIONS
FOR COMORBIDITY

Although researchers have
proposed explanations for the strong association between alcoholism and bipolar
disorder, the exact relationship between these disorders is not well understood.
One proposed explanation is that certain psychiatric disorders (such as bipolar
disorder) may be risk factors for substance use.Alternatively, symptoms
of bipolar disorder may emerge during the course of chronic alcohol intoxication
or withdrawal. For example, alcohol withdrawal may trigger bipolar symptoms.
Still other studies have suggested that people with bipolar disorder may use
alcohol during manic episodes in an attempt at selfmedication, either
to prolong their pleasurable state or to sedate the agitation of mania. Finally,
other researchers have suggested that alcohol use and withdrawal may affect
the same brain chemicals (i.e., neurotransmitters) involved in bipolar illness,
thereby allowing one disorder to change the clinical course of the other. In
other words, alcohol use or withdrawal may "prompt" bipolar disorder symptoms
(Tohen et al. 1998). It remains unclear which if any of these potential mechanisms
is responsible for the strong association between alcoholism and bipolar disorder.
It is very likely that this relationship is not simply a reflection of cause
and effect but rather that it is complex and bidirectional. Genetic factors
may also play a role, as described below.

Familial Risk of Bipolar
Disorder and Alcoholism

The role of genetic factors
in psychiatric disorders has received much attention recently. Some evidence
is available to support the possibility of familial transmission of both bipolar
disorder and alcoholism (Merikangas and Gelernter 1990; Berrettini et al. 1997).
Common genetic factors may play a role in the development of this comorbidity,
but this relationship is complex (Tohen et al. 1998). Preisig and colleagues
(2001) conducted a family study of mood disorders and alcoholism by evaluating
226 people with alcoholism with and without a mood disorder as well as family
members of those people. The researchers found that there was a greater familial
association between alcoholism and bipolar disorder (odds ratio of 14.5) than
between alcoholism and unipolar depression (odds ratio of 1.7). These findings
have implications for prevention and treatment. A positive family history of
bipolar disorder or alcoholism is an important risk factor for offspring.

ISSUES SURROUNDING
THE TREATMENT OF COMORBID BIPOLAR DISORDER AND ALCOHOLISM

This section examines
some of the issues to consider in treating comorbid patients, and a subsequent
section reviews pharmacologic and psychotherapeutic treatment approaches.

Alcoholism's Effect
on Comorbid Bipolar Disorder

A growing number of studies
have shown that substance abuse, including alcoholism, may worsen the clinical
course of bipolar disorder. Sonne and colleagues (1994) evaluated the course
and features of bipolar disorder in patients with and without a lifetime substance
use disorder. They found that compared to nonsubstance abusers, substanceabusing
bipolar patients were more likely to have frequent hospitalizations for affective
symptoms, earlier onset of bipolar disorder, more rapid cycling, and more mixed
mania (the latter two considered to be the most severe, treatmentresistant
forms of bipolar disorder). Keller and colleagues (1986) compared patients who
had pure depression or pure mania with patients who had mixed or rapid cycling
bipolar disorder and found that a higher percentage of patients with mixed or
rapid cycling bipolar disorder had concurrent alcoholism (13 percent) and that
these patients had a slower recovery from the bipolar disorder. Although this
association does not necessarily indicate that alcoholism worsens bipolar symptoms,
it does point out the relationship between them. A comparison of patients with
bipolar disorder and a coexisting substance use disorder with others who had
bipolar disorder alone found that those with comorbid substance use disorders
had an earlier age of onset for their mood disorder, were more likely to be
male, had more comorbid psychiatric disorders in addition to bipolar disorder,
and were significantly more likely to have mixed mania at the time of interview
(Sonne and Brady 1999b).

Although research suggests
that alcohol and other drug abuse may worsen the course of bipolar disorder,
some data indicate that patients with bipolar disorder and alcoholism do better
in substance abuse treatment than alcoholic patients with other mood disorders.
O'Sullivan and colleagues (1988) found that alcoholics with bipolar disorder
functioned better during a 2year followup period than did primary alcoholics
(i.e., those without comorbid mood disorders) or alcoholics with unipolar depression.
This suggests that bipolar patients may use alcohol primarily as a means to
medicate their affective symptoms, and if their bipolar symptoms are adequately
treated, they are able to stop abusing alcohol. Hasin and colleagues (1989)
found that patients with bipolar II disorder were likely to have an earlier
remission from alcoholism compared with patients with schizoaffective disorder
or bipolar I disorder. Researchers have also proposed that the presence of mania
may precipitate or exacerbate alcoholism (Hasin et al. 1985).

In conclusion, it appears
that alcoholism may adversely affect the course and prognosis of bipolar disorder,
leading to more frequent hospitalizations. In addition, patients with more treatmentresistant
symptoms (i.e., rapid cycling, mixed mania) are more likely to have comorbid
alcoholism than patients with less severe bipolar symptoms. If left untreated,
alcohol dependence and withdrawal are likely to worsen mood symptoms, thereby
forming a vicious cycle of alcohol use and mood instability. However, some data
indicate that with effective treatment of mood symptoms, patients with bipolar
disorder can have remission of their alcoholism.

Order of Onset

An important factor in
studying the influence of one comorbid disorder on another is the order of onset
of the two disorders. A mood disorder that occurs prior to the onset of another
psychiatric disorder is called a primary affective disorder. Secondary affective
disorders occur after the onset of other psychiatric disorders. Feinman and
Dunner (1996) conducted a retrospective chart review of three groups of patients:

Those with primary
bipolar disorder with no history of substance abuse (primary group), with
103 patients

Those with primary
bipolar disorder complicated by substance abuse, which began after the onset
of bipolar disorder (complicated group), with 35 patients

Those with bipolar
disorder that came after the onset of substance abuse (secondary group),
with 50 patients.

The researchers found
that patients in the complicated group had a significantly earlier age of onset
of bipolar disorder than the other groups. They also found that the complicated
and secondary groups had higher rates of suicide attempts than did the primary
group. Preisig and colleagues (2001) also reported that the onset of bipolar
disorder tended to precede that of alcoholism. They concluded that this finding
is in accordance with results of clinical studies that suggest alcoholism is
often a complication of bipolar disorder rather than a risk factor for it.

In a 5year followup
study, Winokur and colleagues (1995) evaluated a group of bipolar patients with
and without alcoholism. In the alcoholic patients, bipolar illness and alcoholism
were categorized as being either primary or secondary. The patients with primary
alcoholism had significantly fewer episodes of mood disorder at followup, which
may suggest that these patients had a less severe form of bipolar illness.

Thus, there is growing
evidence that the presence of a concomitant alcohol use disorder may adversely
affect the course of bipolar disorder, and the order of onset of the two disorders
has prognostic implications. Specifically, bipolar patients with secondary alcoholism
may be better able to stop drinking if their bipolar illness is adequately treated;
and, conversely, bipolar patients with primary alcoholism (alcoholism occurs
first) may be better able to control their mood symptoms if they are able to
stop drinking.

Comorbidity and Diagnostic
Issues

Almost every alcoholic
will report having mood swings. It is very important to distinguish these alcoholinduced
symptoms from actual bipolar disorder. However, diagnosing bipolar disorder
in the face of alcohol abuse can be difficult because alcohol use and withdrawal,
particularly with chronic use, can mimic nearly any psychiatric disorder. Alcohol
intoxication can produce a syndrome indistinguishable from mania or hypomania,
characterized by euphoria, increased energy, decreased appetite, grandiosity,
and sometimes paranoia. However, these alcoholinduced manic symptoms generally
occur only during active alcohol intoxication, which makes them fairly easy
to differentiate from mania associated with bipolar I disorder.

Still, alcoholic patients
going through alcohol withdrawal may appear to have depression. Depression is
a key symptom of withdrawal from several substances of abuse, and studies have
demonstrated that symptoms of withdrawalrelated depression may persist
for 2 to 4 weeks (Brown and Schuckit 1988). Because of this phenomenon, it is
likely that observation during lengthier periods of abstinence (i.e., continued
observation following the withdrawal stage) is important for the diagnosis of
depression as compared with mania.

Bipolar II disorder and
cyclothymia are even more difficult to reliably diagnose because of the more
subtle nature of the psychiatric symptoms. Because of the diagnostic difficulties,
it may be that this diagnostic group is often overlooked. Although these less
severe forms of bipolar disorder may not be as disruptive as bipolar I disorder,
it is still important to recognize and treat them in order to break the potential
cycle of mood problems leading to substance use, which leads to a worsening
of mood symptoms, which in turn may worsen the substance abuse, leading to even
worse mood symptoms.

As a general rule, it
seems appropriate to diagnose bipolar disorder if the symptoms clearly occur
before the onset of the alcoholism or if they persist during periods of sustained
abstinence. The adequate amount of abstinence for diagnostic purposes has not
been clearly defined. Family history and severity of symptoms should also factor
into diagnostic considerations. Given that bipolar disorder and substance abuse
cooccur so frequently, it also makes sense to screen for substance abuse
in people seeking treatment for bipolar disorder.

TREATMENT OF COMORBID
BIPOLAR DISORDER AND ALCOHOLISM

In spite of the significant
prevalence of comorbid alcoholism and bipolar disorder, there is little published
data on specific pharmacologic and psychotherapeutic treatments for bipolar
disorder in the presence of alcoholism. The medications most frequently used
for treating bipolar disorder are the mood stabilizers lithium and valproate.
As stated previously, preliminary evidence suggests that alcoholic bipolar patients
may have more rapid cycling and more mixed mania than other bipolar patients.
There is also evidence to suggest that these subtypes of bipolar disorder have
different responses to medications (Prien et al. 1988), which would help provide
a rationale for the choice of agents in the alcoholic bipolar patient. Available
research on the use of lithium, valproate, and naltrexone for comorbid patients
is reviewed below.

Lithium

Lithium has been the standard
treatment for bipolar disorder for several decades. Unfortunately, several studies
have reported that substance abuse is a predictor of poor response of bipolar
disorder to lithium. More specifically, as stated previously, compared to nonsubstance
abusers, alcoholics appear to be at greater risk for developing mixed mania
and rapid cycling. Researchers have found that patients with mixed mania respond
less well to lithium than patients with the nonmixed form of the disorder (Prien
et al. 1988). This suggests that lithium may not be the best choice for a substanceabusing
bipolar patient. However, in a 6week trial of lithium versus placebo in
25 adolescents with bipolar disorder and secondary substance dependence, Geller
and colleagues (1998) found a significant reduction in positive urine tests
for substances of abuse and significant improvement in psychiatric symptoms.
This suggests that lithium may be a good choice for adolescent substance abusers.
The presence of bipolar subtypes was not addressed in this study, so it is not
clear if these adolescents had the subtypes of bipolar illness that are more
difficult to treat.

Valproate

In 1998, the anticonvulsant
Depakote® (also called divalproex sodium, or valproate) was approved
by the Food and Drug Administration (FDA) for the initial treatment of manic
episodes associated with bipolar disorder. Numerous studies have concluded that
patients with mixed or rapid cycling bipolar disorder are more likely to respond
to anticonvulsant medications than to lithium (Bowden 1995). Because, as stated
previously, bipolar patients with concomitant alcoholism appear to have more
mixed or rapid cycling bipolar disorder than do bipolar patients who are not
alcoholic, alcoholic bipolar patients may also respond better to anticonvulsant
medications (e.g., valproate) than to lithium therapy. In fact, in an openlabel
study (i.e., a study in which all participants receive the experimental treatment),
Brady and colleagues (1995) found valproate to be safe and effective in nine
mixedmanic bipolar patients with concurrent substance dependence (primarily
alcohol dependence) who previously had either not tolerated lithium or not responded
to it. Similarly, Albanese and coworkers (2000) reported on 20 patients treated
with divalproex sodium and found that even at fairly low doses divalproex effectively
treated the mood symptoms, and based on selfreport, all patients remained
abstinent during the trial.

Both valproate and alcohol
consumption are known to cause temporary elevations in liver function tests,
and in rare cases, fatal liver failure (Sussman and McLain 1979; Lieber and
Leo 1992). Therefore, the safety of valproate in the alcoholic population has
been questioned because of the potential for hepatotoxicity in patients who
are already at risk for this complication. However, recent preliminary evidence
suggests that liver enzymes do not dramatically increase in alcoholic patients
who are receiving valproate, even if they are actively drinking (Sonne and Brady
1999a). Thus, valproate appears to be a safe and effective medication
for alcoholic bipolar patients.

Naltrexone

Because evidence suggests
that active drinking may worsen bipolar symptoms, it makes sense that medications
designed to decrease alcohol consumption may be useful in bipolar alcoholics.
Naltrexone (ReVia) is an FDAapproved medication designed
to decrease cravings for alcohol. Maxwell and Shinderman (2000) reviewed the
use of naltrexone in the treatment of alcoholism in 72 patients with major mental
disorders, including bipolar disorder and major depression. Eightytwo
percent of patients stayed on naltrexone for at least 8 weeks, 11 percent discontinued
the medication because of side effects, and the remaining 7 percent discontinued
for other reasons. The authors concluded that naltrexone was useful in treating
patients with comorbid psychiatric and alcohol problems. However, Sonne and
Brady (2000) reported on two cases of bipolar women (both actively hypomanic)
who received naltrexone for alcohol cravings, and both had significant side
effects similar to those of opiate withdrawal. Given that there is only preliminary
data on the use of naltrexone in bipolar alcoholics to date, naltrexone should
be used with caution in patients who have been actively hypomanic.

Compliance

Medication compliance
is an important issue to consider when assessing the effectiveness of medications.
One study of the lifetime medication compliance of lithium and valproate in
44 alcohol and other drugabusing bipolar patients found that patients
were significantly more likely to take valproate (50 percent compliant) compared
with lithium (21 percent compliant). Side effects, including lethargy, weight
gain, and tremors, were listed as the main reason for noncompliance with lithium
(Weiss et al. 1998). However, it is also important to note that prescription
bottles for lithium usually have a warning label on them not to drink alcohol
while taking the medication. Thus, if an alcoholic has the choice between taking
lithium or drinking alcohol, it is very likely the alcoholic will not be compliant
with lithium. Increased medication compliance with valproate may be an important
factor in selecting a mood stabilizer for alcoholic bipolar patients.

Psychosocial Interventions

Psychosocial interventions
have often been considered the mainstays of treatment for alcoholism and other
substance use disorders. Several studies have demonstrated success with cognitive
behavioral therapy in treating alcoholism (Project MATCH Research Group 1998).
Many of the principles of cognitive behavioral therapy are commonly applied
in the treatment of both mood disorders and alcoholism. Weiss and colleagues
(1999) have developed a relapse prevention group therapy using cognitive behavioral
therapy techniques for treating patients with comorbid bipolar disorder and
substance use disorder. This therapy uses an integrated approach; participants
discuss topics that are relevant to both disorders, such as insomnia, emphasizing
common aspects of recovery and relapse.

Interestingly, the same
investigators (Weiss et al. 2000) evaluated the progress of a group of substance
abusers with comorbid bipolar spectrum disorders who were pursuing psychosocial
treatment independently, rather than as a result of being assigned to it by
the researchers. Potential study participants were told that the investigators
were interested in better understanding the relationship between bipolar disorder
and substance abuse and therefore wished to see them monthly for 6 months. The
investigators found that psychotherapy and Alcoholics Anonymous (AA) attendance
decreased over time and that substance use tended to increase from month 1 to
month 6. The focus of the study participants' psychotherapy also changed, with
less emphasis on their specific disorders and more emphasis on family, school,
work, and other personal issues. Although differences in mood or substance use
between months 1 and 6 were not statistically significant, there was a trend
for increased substance use. If the study participants had continued with AA
and if psychotherapy had continued to focus on bipolar disorder and alcoholism,
the patients' substance use might have improved. Given the generally poor prognosis
associated with bipolar disorder and alcoholism, it is particularly important
to continuously educate patients concerning the relationship between these two
disorders. The authors concluded that the development of dually focused psychosocial
treatments for this population may help improve substance use and affective
outcomes.

CONCLUSION

Bipolar disorder and alcoholism
commonly cooccur. In two epidemiologic survey studies, alcohol dependence
was more likely to occur with bipolar disorder than with all other psychiatric
disorders except antisocial personality disorder. The nature of the relationship
between alcoholism and bipolar disorder is complex and not well understood.
It appears that alcohol use may worsen the clinical course of bipolar disorder,
making it harder to treat. There is also evidence for a genetic link between
the two conditions. Bipolar disorder complicated by alcoholism is associated
with an increased number of hospitalizations, more mixed mania, earlier age
of onset of bipolar disorder, and more suicidal ideation. Given the prevalence
and morbidity of these two disorders, it is important to screen for substance
abuse in all bipolar patients and to treat aggressively. Unfortunately, there
has been little study of the appropriate treatment of this comorbidity. Several
studies suggest that mood stabilizers (particularly valproate) may work better
than lithium in treating alcoholic bipolar patients, but headtohead
comparison of lithium and valproate has not been carried out. Further study
of this important comorbidity is needed to better understand its course and
treatment.